Association between plasma levels of the soluble CD14 receptor of lipopolysaccharide and the C(-260)→T polymorphism in the promoter of the CD14 gene and coronary artery disease [Elektronische Ressource] : investigations in a large case-control study / Natalie Khuseyinova

Sujets

• Biologie

Informations

• Publié par: universitat_ulm
• Publié le: 01 janvier 2002
• Nombre de lectures: 8
• Langue: English

Extrait

Universität Ulm
Aus der Abteilung Innere Medizin II
Leiter: Prof. Dr. V. Hombach
Association Between Plasma Levels of the
Soluble CD14 Receptor of Lipopolysaccharide
and the C(–260)fiT Polymorphism in the
Promoter of the CD14 Gene and Coronary
Artery Disease: Investigations in a Large Case-
Control Study.
Dissertation zur Erlangung des Doktorgrades der Medizin
der Medizinischen Fakultät der Universität Ulm
vorgelegt von
Natalie Khuseyinova
aus Ashgabat
Turkmenistan
2002
1Amtierender Dekan: Prof. Dr. R. Marre
1. Berichterstatter: Prof. Dr. W. Koenig
2. Berichterstatter: Prof. Dr. T.Simmet
Tag der Promotion: 26.04.2002
2To my family with deep gratitude for its persistent support of my academic
endeavours
3Table of contents:
Abbreviations and Acronyms.................................................................................. 6
1 Introduction....................................... 9
1.1 Coronary artery disease (CAD).................................................................... 9
1.1.1 Pathogenesis of CAD: cellular and molecular interaction ..................... 9
1.1.2 Classical risk factors for CAD............................. 11
1.1.3 CAD – an inflammatory process ......................................................... 15
1.1.4 Possible role of infectious agents in the pathogenesis of CAD........... 16
1.2 CD14 – major receptor for bacterial lipopolysaccharide............................. 18
1.2.1 Chemical structure and biological role of LPS .................................... 18
1.2.2 Mechanism of interaction between LPS and LPS-recognition.................
molecules............................................................................................ 20
1.2.3 Molecular characteristic and functional properties of CD14................ 21
1.2.3.1 Membrane-bound form of CD14.................. 21
1.2.3.2 Soluble form of CD14 .................................................................. 22
1.2.4 Polymorphism of the CD14 gene........................ 23
1.3 Aim of the study ......................................................... 24
2 Material and methods..................................................... 26
2.1 Study design and study population............................ 26
2.2 Data collection................................ 27
2.3 Standardized questionnaire........................................................................ 28
2.4 Coronary angiography................ 29
2.5 Review of patient medical records ............................................................. 30
2.6 Infectious state........................................................... 30
2.6.1 sCD14 ELISA...................... 30
2.6.2 Polymorphism of the CD14 gene ........................................................ 31
2.6.3 Specific anti-H.pylori IgG.................................... 32
2.6.4 IgG antibodies against Chlamydia...................... 32
2.7 Sensitive systemic markers of inflammation and hemostasis and lipids
parameters................................................................................................. 32
2.8 Data management and statistical analysis ................................................. 36
3 Results............................................................................ 38
3.1 Study population........................ 38
43.2 Association between the C(-260)fiT polymorphism, sCD14 plasma levels,
and presence of CAD................................................................................. 41
3.3 Association between sCD14 plasma levels and C(-260)fiT polymorphism
of the CD14 gene....................... 43
3.4 Association between sCD14 plasma levels and serostatus of Chlamydia
pneumoniae and serostatus of Helicobacter pylori..................................... 47
3.5fiT polymorphism
of the CD14 gene and various markers of inflammation and hemostasis .. 48
3.5.1 Association between sCD14 plasma levels and various markers of
inflammation and hemostasis.............................................................. 48
3.5.2 Association between C(-260)fiT polymorphism of the CD14 gene and
and various markers of inflammation and hemostasis ........................ 50
3.6 Association between sCD14 plasma levels and C(-260)fi T polymorphism
of the CD14 gene and severity and extension of CAD............................... 52
4 Discussion ...................................................................................................... 54
4.1 Association between CD14 genotype and CAD......... 54
4.2 Association between sCD14 plasma levels and CAD 57
4.3 Association between CD14 genotype and sCD14 plasma levels............... 58
4.4 Association between CD14 genotype, sCD14 plasma levels, and sensitive
systemic markers of inflammation.............................................................. 59
4.5 Association between CD14 genotype, sCD14 plasma levels, and severity of
CAD ........................................................................................................... 59
4.6 Strengths and limitations of the present study............ 60
4.7 Conclusions….……………………………..……………………………………62
5 Summary ........................................................................................................ 63
6 Appendix......... 65
7 References..... 89
8 Acknowledgments......................................................................................... 106
5Abbreviations and Acronyms
AMI acute myocardial infarction
AP angina pectoris
apo B-100 apolipoprotein B-100
BMI body mass index
bp base pair
CAD coronary artery disease
CAM cellular adhesion molecule
CD14 cluster of differentiation antigen 14
CD36 cluster of differentiation antigen 36
cDNA complementary DNA
CI confidence interval
CMV Cytomegalovirus
C. pneumoniae Chlamydia pneumoniae
CRP C-reactive protein
dNTP deoxynucleoside triphosphate
EC endothelial cell
ECG electrocardiogram
e.g. for example
ELAM endothelial leukocyte adhesion molecule
ELISA enzyme-linked immunosorbent assay
ERA Estrogen Replacement and Atherosclerosis
ESR erythrocyte sedimentation rate
et al et alii
FDP fibrin degradation product
FGF fibroblast growth factor
GM-CSF granulocyte-macrophage colony-stimulating factor
GPI glycosylphosphatidilinositol
Hb A hemoglobin A1c 1c
HERS Heart and Estrogen/Progestin Replacement Study
HLD high density lipoprotein
HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A
HPETE hydroperoxyeicosatetraenoic acid
6H. pylori Helicobacter pylori
HRT hormone replacement therapy
HSP heat shock protein
HSV Herpes simplex virus
ICAM-1 intercellular adhesion molecule-1
i.e. id est
IgG immunoglobulin G
INF-g interferon-g
IL interleukin
IRMA immunoradiometric assay
kDa kilo Dalton
LBP lipopolysaccharide-bind protein
LDL low density lipoprotein
Lp (a) lipoprotein (a)
LPS lipopolysaccharide
12-LO 12/15 lipoxygenase
mAb monoclonal antobody
MCP-1 monocyte chemotactic protein-1
M-CSF macrophage colony-stimulating factor
mm-LDL minimally oxidized low density lipoprotein
MRFIT Multiple Risk Factor Intervention Trial
NO nitric oxide
NFB nuclear factor-kappa B
¯
O superoxid anion2
OD optical density
OR odds ratio
ox-LDL highly oxidized low density lipoprotein
PAI-1 plasminogen activator inhibitor-1
PAOD peripheral arterial occlusive disease
PCR polymerase chain reaction
PDGF platelet-derived growth factor
PHS Physicians‘ Health Study
PLC phospholipase C
7PNH paroxysmal nocturnal hemoglobinuria
PROCAM Prospective Cardiovascular Münster Study
RAS renin-angiotensin system
RH relative hazard
ROS reactive oxygen species
RR risk ratio
SAA serum amyloid A
SAS statistical analysis system
SMC smooth muscle cell
SR-A scavenger receptor-A
TIA transient ischemic attack
TF tissue factor
TGF-b transforming growth factor-b
TLR-4 Toll like receptors-4
TNF-a tumor necrosis factor-a
VCAM-1 vascular adhesion molecule-1
VLA-4 very late antigen-4
VLDL very low density lipoprotein
vs versus
vWF von-Willebrand factor
UKPDS United Kingdom Prospective Diabetes Study
81 Introduction
1.1 Coronary artery disease (CAD)
1.1.1 Pathogenesis of CAD: cellular and molecular interactions
In the “response to injury” hypothesis of atherosclerosis, endothelial dysfunction
represents an initial step for the early local inflammation which precedes plaque
development (Ross 1999). The endothelium, with its intercellular tight junctional
complexes, functions as a selective permeable barrier between the vessel wall and
circulating blood. As one of the important physical forces acting on endothelial cells
(EC), fluid shear stress has an effect on EC morphology and therefore can
determine, in part, the site of an atherosclerotic lesion (Koenig & Hombach 1995).
It has been well established that atherosclerotic lesions typically develop in the
vicinity of branch points and areas of major curvature, where blood flow is non-
laminar. ECs in those areas have polygonal shapes and no particular orientation
that would increase permeability of the endothelium to macromolecules like low
density lipoproteins (LDL). In contrast, ECs in the tubula